Project 2: Targeting metabolic vulnerabilities in glioblastoma SUMMARY/ABSTRACT Glioblastoma (GBM) is one of the most lethal of all cancers. As such, new therapeutic strategies are desperately needed. We and others have shown that metabolic reprogramming is a key feature of GBM to accommodate the heightened energetic, nutrient and redox requirements to support tumor growth and survival. The most prominent characteristics of this metabolic reprogramming are a shift to high glycolytic flux. Recent evidence suggests that oncogenic signaling regulates glycolytic flux in GBM. Accordingly, inhibition of oncogenic signaling can disrupt glycolysis, leading to reduced metabolic intermediates for cellular energetic and anabolic processes. However, the therapeutic potential of targeting oncogene-regulated glycolysis in GBM remains enigmatic. We present compelling preliminary data demonstrating that acute inhibition of EGFR ? the most frequently altered oncogene in GBM - can rapidly and potently attenuate glucose uptake and, consequently, glycolytic flux in GBM. As a result of this ?altered? metabolic state, GBM models show synergistic lethality to pharmacological p53 activation. We also demonstrate that 18F-flurodeoxyglucose (FDG) and positron emission tomography (PET) can be used as a rapid (within hours), non-invasive biomarker that may predict sensitivity to this new combination approach. In this proposal, we expand on these exciting preliminary findings. In Aim 1, we will investigate whether combined targeting of EGFR-regulated glycolysis (e.g., pulsatile Erlotinib) and p53 activation (e.g., Idasanutlin) is efficacious in straight-from-patient orthotopic GBM xenografts. We will also determine whether 18F-FDG PET can serve as a robust predictive biomarker for sensitivity to this drug combination. In Aim 2, we propose to interrogate the underlying mechanism of the unexpected role of p53 in eliciting apoptosis under pharmacological glycolytic attenuation. Finally, in Aim 3, we propose a clinical trial to test whether EGFR inhibition combined with a novel p53 activator (Idasanutlin, provided by Roche?) is safe and efficacious in recurrent GBM patients. Incorporated into this trial is the evaluation of 18F-FDG PET as a non-invasive and early predictor of efficacy to this new approach to targeting GBM metabolism. The studies proposed in this application present a new combination strategy through specific manipulation of metabolism and apoptotic pathways in malignant glioma and have the long-term potential to shift current approaches in glioma therapy.